
==== Front
J Atheroscler Thromb
J Atheroscler Thromb
jat
Journal of Atherosclerosis and Thrombosis
1340-3478
1880-3873
1340-3478
Japan Atherosclerosis Society

39010219
DN/JST.JSTAGE/jat/RV22021
10.5551/jat.RV22021
RV22021
Review
The Association between Dyslipidemia and Pulmonary Diseases
Isago Hideaki 1
1 Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
Address for correspondence:Hideaki Isago, Department of Clinical Laboratory, The University of Tokyo Hospital, 7-3-1 Hongo Bunkyo-ku Tokyo 113-8655, Japan E-mail: ISAGOH-INT@h.u-tokyo.ac.jp
1 9 2024
12 7 2024
31 9 12491259
29 5 2024
28 5 2024
2024 Japan Atherosclerosis Society
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.http://creativecommons.org/licenses/by-nc-sa/4.0/
Dyslipidemia is one of the most common diseases worldwide. As a component of metabolic syndrome, the prevalence and mechanism by which dyslipidemia promotes cardiovascular diseases has been well studied, although the relationship between pulmonary diseases is not well understood. Because the lung is a respiratory organ with a large surface area and is exposed to the environment outside the body, it continuously inhales various substances. As a result, pulmonary diseases have a vast diversity, including chronic inflammatory diseases, allergic diseases, cancers, and infectious diseases. Recently, growing evidence has suggested that dyslipidemia plays a role in the pathogenesis and prognosis of various pulmonary diseases. We herein review the current understanding of the relationship between dyslipidemia and pulmonary diseases, including chronic obstructive pulmonary diseases, asthma, and lung cancer, and infectious pulmonary diseases, including community-acquired pneumonia, tuberculosis, nontuberculous mycobacterial pulmonary disease, and COVID-19. In addition, we focus on recent evidence of the utility of statins, specifically 3-hydroxy-3-methylglutaryl-coA reductase inhibitors, in the prevention and treatment of the various pulmonary diseases described above.

Dyslipidemia
Pulmonary diseases
Statins
Metabolic syndrome
==== Body
pmc1.Introduction

The lungs are major organs of the respiratory system that enable gas exchange between inhaled air and circulating blood. As they have a large surface area (approximately 70 m2 in adults) and are constantly exposed to the environment outside of the body 1) , various stimulations (pathogens, toxic substances, and allergens) cause pulmonary diseases, including infectious diseases, allergic diseases, chronic inflammatory diseases, and cancers.

Metabolic syndrome (MetS) is a cluster of risk factors, including hypertension, dyslipidemia, raised fasting glucose, and central obesity 2) . Patients with MetS are susceptible to cardiovascular disease and type 2 diabetes mellitus. Dyslipidemia is defined as an imbalance of plasma lipids and/or lipoproteins, such as triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Dyslipidemia is the most notable risk factor for cardiovascular disease 3) , and its prevalence has increased worldwide over the past 30 years 4) . However, its relationship with pulmonary diseases is not well understood.

Statins, specifically 3-hydroxy-3-methylglutaryl-coA reductase inhibitors, are commonly used in the treatment of dyslipidemia because of their inhibitory effect on cholesterol synthesis 5) . Furthermore, statins have been reported to have anti-inflammatory and immunomodulatory effects (“pleiotropic” effects), mainly related to the inhibition of protein isoprenylation. As statins inhibit the synthesis of L-mevalonate, the production of downstream metabolites of L-mevalonate, including farnesyl pyrophosphate and geranylgeranyl pyrophosphate, is inhibited. These two molecules are essential for the activation of small GTPase proteins, including Ras, Rho, and Rac, via post-transcriptional isoprenylation. Because the activation of these cell signaling proteins is involved in cell differentiation, proliferation, and inflammation, statins are expected to contribute to the treatment of various diseases 6) .

In the present review, we explore the current understanding of the relationship between dyslipidemia and pulmonary diseases, including chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), lung cancer, and infectious pulmonary diseases, as well as the clinical implications of statins for their prevention and treatment.

2.Relationship between Dyslipidemia and Respiratory Diseases

2.1 COPD

COPD is a heterogeneous lung condition characterized by chronic respiratory symptoms (dyspnea, cough, expectoration, and/or exacerbations) due to abnormalities of the airways and/or alveoli, which cause persistent, often progressive, airflow obstruction 7) . It is estimated that the global prevalence of COPD among people aged 30-79 years was 7.6% (391.9 million people) in 2019 8) . Although primarily caused by cigarette smoking, the progression of COPD depends on numerous interacting environmental, genetic, and developmental factors 7 , 9) .

COPD is also known to be a systemic inflammatory disease, and smoking-induced endothelial injury caused by oxidative stress is gaining attention as an additional contributor not only to the pathogenesis of COPD, but also to the pathogenesis of systemic comorbidities, including atherosclerosis, pulmonary hypertension, and chronic renal injury 10) .

Dyslipidemia, the most common risk factor for cardiovascular disease, is one of the most common comorbidities in COPD patients 11) . However, whether or not it affects COPD progression remains unknown. Recently, a nationwide population study cohort study in Taiwan, which enrolled more than 100,000 patients from the National Health Insurance Research Database, reported that patients with hyperlipidemia were more likely to develop subsequent COPD than those without hyperlipidemia 12) . Although this study had several limitations, including confounders, which are inevitable in registry-based studies, this evidence may support a link between the progression of COPD and dyslipidemia through endothelial injury 10) ( Fig.1 ) .

Fig.1. The pathogenesis of COPD and dyslipidemia

Among the many comorbidities accompanied by COPD, cardiovascular diseases frequently coexist with COPD 13) and are associated with increasing mortality, which accounts for 16%-39% of death in COPD patients 14) . Interestingly, in the Hokkaido COPD Cohort study in Japan, cardiovascular diseases accounted for only 11% of deaths in COPD patients, which is significantly lower than that in Western countries 15) . Adiponectin has gained attention for explaining this difference. Adiponectin is an adipocytokine released from adipose tissue. Adiponectin has anti-inflammatory and antioxidative properties and is known to be higher in underweight populations than obese populations 16) . Tomoda et. al reported that plasma adiponectin levels are four times higher in COPD patients than in controls and two times higher even in normal weight COPD patients in Japan 17) . In addition, serum adiponectin has been reported to be inversely associated with cardiovascular events in patients 18) . As the underweight and non-obese phenotype of COPD is dominant in Japan 19) , it is estimated that Japanese patients with COPD have relatively high levels of serum adiponectin, which might explain their lower rate of cardiovascular events than patients in Western countries.

Regarding whether or not the use of statins to treat dyslipidemia and anti-inflammatory therapy would improve the outcomes of COPD, many observational studies have reported conflicting results, possibly due to the influence of major biases 20) . Of the two randomized control studies that have been conducted, one reported that simvastatin had no effect on COPD exacerbation 21) , while the other reported that simvastatin prolonged the time to first COPD exacerbation and reduced exacerbation frequency 22) . Further studies are required to elucidate the precise effects of statins on COPD treatment.

2.2 Asthma

Asthma is one of the most common chronic, non-communicable diseases, affecting 4.3% of adults worldwide 23) and accounting for 1 in every 250 deaths worldwide 24) . Asthma is a heterogeneous and multifactorial disease characterized by variable respiratory symptoms (cough, chest tightness, shortness of breath, and wheezing) and airflow limitation. These symptoms are typically caused by chronic airway inflammation, hypersensitivity, and remodeling. Pathologically, eosinophilic, type 2-high airway inflammation accounts for approximately 50% of adult asthma cases, although some asthma cases exhibit type 2-low airway inflammation, represented by neutrophilic inflammation 23) . Various types of cells are involved in asthma inflammation, including T cells, macrophages, granulocytes, B cells, and lipid mediators, such as leukotrienes, prostaglandins, and fatty acids, regulate cell signaling between these cells 25) . Among lipid mediators, leukotrienes play an important role in the pathogenesis of asthma 26) , and leukotriene receptor antagonists, such as montelukast, play an important role in the pharmacological treatment of asthma 23) .

Although inhaled corticosteroids significantly improved the treatment of asthma in the 20th century, whether or not certain types of asthma patients, particularly obese patients, respond to traditional corticosteroid therapy remains unclear 27) . In addition, the prevalence of asthma in the obese population is twice as high as that in the normal-weight population 28) . Hence, the relationship between obesity and asthma has been extensively studied. Many explanations have been proposed for the complex interactions between asthma and obesity, including developmental factors, genetic factors, mechanical factors, systemic inflammation, metabolic inflammation, and oxidative stress 29) . Among these, MetS has recently become the focus of research. A small study reported that adult-onset asthma is associated with MetS independent of the body mass index (BMI) 30) . In addition, an explorative study reported that elevated serum TGs levels were independently associated with asthma in obese patients, suggesting the role of dyslipidemia in the pathogenesis of asthma 31) . More recently, a retrospective cohort study reported that elevated triglyceride-glucose index, a biomarker of metabolic dysfunction calculated from fasting TG and fasting glucose, was an independent predictor of severe asthma exacerbation 32) . Accumulating evidence suggests a link between asthma and dyslipidemia, especially high TG levels, although the mechanism by which elevated TG levels affect the pathogenesis of asthma remains unknown.

Considering their anti-inflammatory and immune-modulating effects, statins appear to be a promising pharmacological treatment for severe asthma. Indeed, a study in an animal model of obesity-related asthma revealed that pravastatin exerts anti-asthmatic effects by suppressing the Th2 and Th17 signaling pathways 33) . Many RCTs focusing on statin effects on asthma have been conducted, and recently, a meta-analysis of 12 RCTs reported that statins did not alter the lung function in patients with asthma but did improve asthma symptoms and inflammatory indexes in blood and sputum 34) .

2.3 IPF

IPF is the most common idiopathic interstitial pneumonia with a poor prognosis. The prevalence of IPF ranges from 10 to 60 cases per 100,000 35) and is 10.0 in Japan 36) . IPF is characterized by severe, chronic, progressive, and irreversible pulmonary fibrosis that occurs in the lung parenchyma. The median survival time of patients with IPF is less than five years. Despite extensive research, the precise pathogenesis of IPF remains obscure, but according to our current understanding, the fibrosis of IPF is generated by recurrent of chronic epithelial-cell injury, which leads to aberrant wound healing 37) . Aside from lung transplantation, there is no fundamental treatment for IPF. However, in the last decade, two antifibrotic agents, pirfenidone and nintedanib, have been shown to mitigate the progression of fibrosis and have been approved 38 , 39) .

Although the exact causes of IPF remain unknown, several potential risk factors have been identified, including cigarette smoking, occupational and environmental inhalation of particles (chemical fumes, dust, etc.), viral infections, and comorbidities, such as gastroesophageal reflux, diabetes mellitus, and obstructive sleep apnea 37) . As both IPF and dyslipidemia frequently occur in elderly patients, whether or not dyslipidemia affects IPF progression is unclear. In a systematic review, the prevalence of hyperlipidemia in IPF patients ranged from 6% to 53% 40) . A recent nationwide cohort study in South Korea reported that the prevalence of dyslipidemia in IPF patients was 50.49% at the diagnosis, second only to gastroesophageal reflux disease 41) . However, to our knowledge, no relationship has been identified between IPF pathogenesis and dyslipidemia.

Statins are expected to mitigate the progression of pulmonary fibrosis through pleiotropic effects. Many observational clinical studies and basic research have been conducted to date; however, they have shown inconclusive results 42) . Recently, two studies based on South Korea’s database of the National Health Insurance Service reported that the use of statins had beneficial effects on IPF, including lowering the risk of IPF and improving mortality in IPF patients 43 , 44) . However, a large-scale prospective study is needed to elucidate the precise effects of statins on IPF.

2.4 Lung Cancer

Lung cancer is now the most frequently diagnosed cancer and the leading cause of cancer-related deaths worldwide 45) . Despite recent advances in treatment, including oncogenic alteration-specific molecular-targeted agents and immunotherapies using immune checkpoint inhibitors (ICIs) 46) , the 5-year survival from lung cancer tends to be below 20% in most countries 45) .

Although cigarette smoking is the strongest risk factor for lung cancer, a small proportion of the population develops lung cancer despite no history of smoking 47) . In addition, despite a decrease in the size of the smoking population, the incidence of lung cancer is increasing, suggesting the potential presence of other as-yet-unidentified risk factors.

Recently, the association between lung cancer and MetS, including dyslipidemia, has been extensively studied, and several cohort studies have reported that high levels of TG and low levels of HDL-C are associated with the risk of lung cancer 48 - 50) . Some hypotheses have been proposed to explain this, including the suggestion that oxidative stress and reactive oxygen species caused by high TG levels promote carcinogenesis, while low HDL-C levels abolish the anti-inflammatory, antioxidant, and anti-proliferative effects of HDL-C 50) .

More recently, a prospective cohort study on the UK biobank, which enrolled 331,877 people, reported that the hazard ratio of MetS was 1.21 (95% confidence interval [CI], 1.09-1.33) for the overall risk of lung cancer, and a positive association with lung cancer was observed for low levels of HDL-C, an increased waist circumference, and hyperglycemia 51) . Previous studies have demonstrated that an excessive BMI acts as a protective factor against lung cancer 52) , as in Japan 53) , although its biological mechanism remains unknown. However, even with a careful analysis, the confounding effect of smoking was unavoidable in these studies 52 , 53) . In the present study, the same association between lung cancer and the BMI was observed; however, after controlling for the BMI, an increased waist circumference was still identified as a risk factor for lung cancer. The authors speculated that abdominal adiposity may be an important risk factor for promoting carcinogenesis through hyperinsulinemia, altered levels of sex hormones, and proinflammatory adipokines 51) . Although further studies are needed, the perspective of abdominal adiposity may contribute to the understanding of the relationship between MetS and lung cancer ( Fig.2 ) .

Fig.2. Lung cancer and metabolic syndrome

Similar to other cardiovascular/anti-inflammatory drugs, the effect of statins for treating or preventing cancers is also of interest, although a meta-analysis could not validate the beneficial effects 54) . In lung cancer, one observational study reported that statin use was positively correlated with the prognosis of patients receiving immunotherapy by ICIs, which the authors speculated on the synergy of the immunomodulatory effects of statins and ICIs 55) . Another study of South Korea’s National Health Insurance Service database suggested that statins have an independent protective association with lung cancer development in patients with IPF 43) . Further studies are expected to reveal the effective use of statins in the clinical management, prevention, and treatment of lung cancer.

2.5 Infectious Diseases

2.5.1 Community-Acquired Pneumonia (CAP)

CAP is defined as pneumonia acquired outside a hospital. It is usually caused by a bacterial infection, represented by Streptococcus pneumoniae 56) , although viruses or fungi can be responsible for this 57) . Despite advances in antimicrobial agents, lower respiratory tract infections, including pneumonia (excluding COVID-19), remain the fifth leading cause of death as of 2021 58) . In Japan, the estimated incidence rates of adult CAP, hospitalization, and in-hospital death are 16.9, 5.3, and 0.7 per 1,000 person-years, respectively 59) .

Many risk factors for CAP have been identified, including age, sex, lifestyle, and comorbidities. Dyslipidemia has not yet been identified as a risk factor for CAP 60) . However, in the study of sepsis, growing evidence has highlighted the importance of plasma cholesterol in severe bacterial infections. A meta-analysis reported hypocholesterolemia, including total cholesterol, HDL-C, and LDL-C to be associated with a poor prognosis in sepsis 61) , and another meta-analysis found that hypocholesterolemia, especially low HDL-C levels, is associated with increased mortality due to sepsis 62) , although the mechanism is not well understood.

Regarding the relevance of plasma cholesterol levels to severe CAP, a small study reported that hypocholesterolemia was associated with increased mortality from severe CAP 63) . Although not limited to CAP, a large cohort study from the Mayo Clinic reported that, among patients hospitalized with pneumonia, those diagnosed with hyperlipidemia showed lower short- and long-term mortality than those not diagnosed with hyperlipidemia, and LDL-C levels were inversely associated with mortality 64) . These findings suggest that the plasma cholesterol level is a promising prognostic factor for CAP ( Fig.3A ) .

Fig.3. Pulmonary infectious diseases and dyslipidemia A: Dyslipidemia and community-acquired pneumonia. B: Dyslipidemia and tuberculosis. C: Dyslipidemia and COVID-19.

Numerous observational studies have been conducted to clarify whether or not statins have beneficial effects in the prevention or treatment of CAP, but the results have been inconsistent and conflicting 65 , 66) . Considering that the utility of statins in sepsis has not been established 61) , more studies are needed to elucidate the role of statins in CAP treatment.

2.5.2 Tuberculosis

Tuberculosis is an airborne infectious disease caused by Mycobacterium tuberculosis infection, which mainly targets the lungs and is transmitted through the air 67) . Although tuberculosis is now a preventable and usually curable disease, it remained the world’s second leading cause of death from a single infectious agent, after coronavirus disease 2019 (COVID-19), in 2022, and it is estimated that more than 10 million people will become ill and 1.30 million people will die from tuberculosis every year 67) . Furthermore, with the emergence of multidrug-resistant tuberculosis, which is resistant to current tuberculosis drugs 68) , it remains a public health threat in most parts of the world.

After inhalation, M. tuberculosis is phagocytosed by the alveolar macrophages. While it evades the antimicrobial activity of macrophages by inhibiting phagosome-lysosome fusion, host immunity contains infected macrophages within granulomas and limits bacterial growth 69) .

The risk of tuberculosis in immunocompromised hosts, such as patients with AIDS or solid organ transplantation, has been well recognized and studied 70) . However, the relationship between tuberculosis and dyslipidemia is poorly understood. Ngo et al. summarized the current understanding of the association between dyslipidemia and tuberculosis 71) . Interestingly, observational studies have shown that susceptibility to tuberculosis, unlike other inflammatory pulmonary diseases, low total cholesterol is associated with an increased risk of tuberculosis 72) , and low total cholesterol, low HDL-C, and low LDL-C levels are associated with extensive lung lesions of pulmonary tuberculosis infection 73 , 74) . In addition, another study reported that elevated levels of cholesterol are associated with reduced systemic inflammation and mortality in pulmonary tuberculosis, independent of the BMI 75) . These studies strongly suggest that serum cholesterol levels are protective against tuberculosis infection. The mechanism by which serum cholesterol affects tuberculosis infection is elusive, although several studies have suggested that cholesterol plays an essential role in the phagocytosis of macrophages 76 , 77) ( Fig.3B ) .

If low cholesterol levels affect the course of pulmonary tuberculosis, does a high-cholesterol diet or treatment for dyslipidemia affect the course as well? A high-cholesterol diet has shown adverse results so far, as a large cohort study in Singapore reported a dose-dependent relationship between a high-cholesterol diet and active tuberculosis 78) , while a small RCT study reported that a cholesterol-rich diet accelerated the sterilization rate of sputum cultures in patients with pulmonary tuberculosis 79) . Regarding statin treatment, a study on the South Korean nationwide database reported no protective effect of statins against tuberculosis 80) , while a study on Taiwan’s national database reported a positive relationship between statin use and lower risk of tuberculosis 81) . Further studies are required to confirm these findings.

2.5.3 Nontuberculous Mycobacterial Pulmonary Disease (NTM PD)

NTM PD is a non-communicable, chronic infectious pulmonary disease caused by nontuberculous mycobacterial infection, representing over 190 species and subspecies from ubiquitous environment 82) . The prevalence of NTM PD is increasing worldwide, especially in Asia 83) . As biological agents are widely used in the treatment of immune-mediated inflammatory diseases, the rise in NTM infection as a severe adverse event is a concern 84) . Importantly, as the clinical course of NTM PD varies widely depending on the species of NTM and the immune system of hosts, the treatment of NTM PD has not yet been established 82) . Therefore, precise identification of risk factors and improved treatment of NTM are required.

There are several known risk factors for NTM PD, including the environment (e.g. isolation of NTM in showerheads, humidity), structural lung disease, genetic disorders, and impaired immunity 85) . Clinically, it has been documented that thin, older women are predisposed to NTM PD, which is referred as “Lady Windermere Syndrome” 86) . Regarding dyslipidemia, a case-control, retrospective study first reported the relationship between NTM PD and the level of serum total cholesterol, which was significantly lower in patients with NTM PD than in those without it 87) . In addition, in patients with disease progression, which is defined by radiological exacerbation and positive sputum culture, the total cholesterol level tended to decrease as the disease progressed, suggesting the usefulness of total cholesterol level as a predictor of disease progression 87) . The mechanism underlying the relationship between the level of total cholesterol and NTM PD is uncertain, but one possible explanation is that a low total cholesterol level reflects the host’s malnutrition, as other studies have suggested that a low BMI 88) , low visceral fat, and low nutrient intake 89) are associated with NTM PD.

The treatment of NTM PD varies depending on the species, but in general, regimens include a combination of several kinds of antibiotics 82) . To our knowledge, the utility of statins has not been confirmed in any clinical studies so far; however, basic evidence suggests the effectiveness of statins in NTM PD treatment via a mechanism common with tuberculosis 90) .

2.5.4 COVID-19

Since the emergence of SARS-CoV-2 in 2019, COVID-19 has rapidly spread worldwide, evolving into a pandemic, and remains a significant international threat to public health. As the pandemic has been on a downward trend, the World Health Organization declared COVID-19 no longer a global health emergency in 2023 91) . However, the risk of the emergence of new variants remains.

In the early stage of the pandemic, the risk of severe acute respiratory syndrome and mortality in patients with COVID-19 was quite high, so the risk factors correlated with the severity and mortality of COVID-19 have been extensively researched. Among the identified risk factors, MetS has been associated with adverse COVID-19 outcomes 92 , 93) . As for dyslipidemia, a meta-analysis reported that the prevalence of dyslipidemia increased the mortality and severity of COVID-19 94) , and an umbrella review reported that a history of dyslipidemia was likely associated with the severity of COVID-19. They also warned about the ambiguity of the definition of dyslipidemia in previous studies 95) .

The precise mechanism by which dyslipidemia affects the COVID-19 prognosis remains unknown. One possible explanation for this is that viruses, including SARS-CoV-2, use lipid membranes not only as entry points for host cells but also as viral membranes; therefore, the level of cholesterol may affect the efficiency of viral replication 96) ( Fig.3C ) .

During the pandemic, vigorous research was poured into identifying widely available and inexpensive drugs that might improve the outcome of COVID-19. Among them, statins were found to be particularly promising, owing to their anti-inflammatory effects. Many favorable relationships aligned with these data have been reported from multiple observational studies, and a meta-analysis reported that statin use improved mortality, intensive-care unit admission, and mechanical ventilation rates 97) . This effect on mortality was preserved in a meta-analysis of propensity-matched cohorts 98) . Recently, the results of an international multicenter RCT that administered simvastatin to critically ill COVID-19 patients from October 2020 to January 2023 were reported. The primary outcome was organ support-free days, and although it did not meet the prespecified criteria, initiation of simvastatin was superior to the control at a probability of 95.9% 99) . Despite the promising results of this study, however, verification of the effectiveness of statins in COVID-19 treatment might no longer be possible, as the number of severe COVID-19 cases has already dramatically decreased. However, these data may be able to be utilized in future pandemics of infectious pulmonary diseases.

3.Conclusions

This review summarizes the latest understanding of the relationship between dyslipidemia and pulmonary diseases and the current knowledge of the effects of statins on pulmonary diseases. Growing evidence from clinical studies as well as basic research suggests the importance of lipidomics in pulmonary diseases and the potential effectiveness of statins. Although further studies are needed, lipidomic approaches appear to be promising for the prevention and treatment of pulmonary disease.

Conflicts of Interest

None.
==== Refs
1) Angelidis I, Simon LM, Fernandez IE, Strunz M, Mayr CH, Greiffo FR, Tsitsiridis G, Ansari M, Graf E, Strom TM, Nagendran M, Desai T, Eickelberg O, Mann M, Theis FJ and Schiller HB: An atlas of the aging lung mapped by single cell transcriptomics and deep tissue proteomics. Nat Commun, 2019; 10: 963
2) Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM and Smith SC, Jr.: Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation, 2009; 120: 1640-1645
3) Michos ED, McEvoy JW and Blumenthal RS: Lipid Management for the Prevention of Atherosclerotic Cardiovascular Disease. N Engl J Med, 2019; 381: 1557-1567
4) Pirillo A, Casula M, Olmastroni E, Norata GD and Catapano AL: Global epidemiology of dyslipidaemias. Nat Rev Cardiol, 2021; 18: 689-700
5) Adhyaru BB and Jacobson TA: Safety and efficacy of statin therapy. Nat Rev Cardiol, 2018; 15: 757-769
6) Dehnavi S, Sohrabi N, Sadeghi M, Lansberg P, Banach M, Al-Rasadi K, Johnston TP and Sahebkar A: Statins and autoimmunity: State-of-the-art. Pharmacol Ther, 2020; 214: 107614
7) Agustí A, Celli BR, Criner GJ, Halpin D, Anzueto A, Barnes P, Bourbeau J, Han MK, Martinez FJ, Montes de Oca M, Mortimer K, Papi A, Pavord I, Roche N, Salvi S, Sin DD, Singh D, Stockley R, López Varela MV, Wedzicha JA and Vogelmeier CF: Global Initiative for Chronic Obstructive Lung Disease 2023 Report: GOLD Executive Summary. Arch Bronconeumol, 2023; 59: 232-248
8) Adeloye D, Song P, Zhu Y, Campbell H, Sheikh A and Rudan I: Global, regional, and national prevalence of, and risk factors for, chronic obstructive pulmonary disease (COPD) in 2019: a systematic review and modelling analysis. Lancet Respir Med, 2022; 10: 447-458
9) Lange P, Ahmed E, Lahmar ZM, Martinez FJ and Bourdin A: Natural history and mechanisms of COPD. Respirology, 2021; 26: 298-321
10) Polverino F, Celli BR and Owen CA: COPD as an endothelial disorder: endothelial injury linking lesions in the lungs and other organs? (2017 Grover Conference Series). Pulm Circ, 2018; 8: 2045894018758528
11) Divo M, Cote C, de Torres JP, Casanova C, Marin JM, Pinto-Plata V, Zulueta J, Cabrera C, Zagaceta J, Hunninghake G and Celli B: Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2012; 186: 155-161
12) Yang HY, Hu LY, Chen HJ, Chen RY, Hu CK and Shen CC: Increased Risk of Chronic Obstructive Pulmonary Disease in Patients with Hyperlipidemia: A Nationwide Population-Based Cohort Study. Int J Environ Res Public Health, 2022; 19: 12331
13) Wang B, Zhou Y, Xiao L, Guo Y, Ma J, Zhou M, Shi T, Tan A, Yuan J and Chen W: Association of lung function with cardiovascular risk: a cohort study. Respir Res, 2018; 19: 214
14) Berry CE and Wise RA: Mortality in COPD: causes, risk factors, and prevention. Copd, 2010; 7: 375-382
15) Makita H, Suzuki M, Konno S, Shimizu K, Nasuhara Y, Nagai K, Akiyama Y, Fuke S, Saito H, Igarashi T, Takeyabu K and Nishimura M: Unique Mortality Profile in Japanese Patients with COPD: An Analysis from the Hokkaido COPD Cohort Study. Int J Chron Obstruct Pulmon Dis, 2020; 15: 2081-2090
16) Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T and Matsuzawa Y: Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun, 1999; 257: 79-83
17) Tomoda K, Yoshikawa M, Itoh T, Tamaki S, Fukuoka A, Komeda K and Kimura H: Elevated circulating plasma adiponectin in underweight patients with COPD. Chest, 2007; 132: 135-140
18) Yoon HI, Li Y, Man SFP, Tashkin D, Wise RA, Connett JE, Anthonisen NA, Churg A, Wright JL and Sin DD: The Complex Relationship of Serum Adiponectin to COPD Outcomes. Chest, 2012; 142: 893-899
19) M. Yoshikawa HK: Chronic Obstructive pulmonary disease (COPD): progress in diagnosis and treatment topics: III. Complications: 1. Nutritional impairment in patients with COPD. Naika Gakkai Zasshi, 2012; 101: 1562-1570
20) Sule NO and Suissa S: Statins and Mortality in COPD: A Methodological Review of Observational Studies. Copd, 2023; 20: 284-291
21) Criner GJ, Connett JE, Aaron SD, Albert RK, Bailey WC, Casaburi R, Cooper JA, Jr., Curtis JL, Dransfield MT, Han MK, Make B, Marchetti N, Martinez FJ, Niewoehner DE, Scanlon PD, Sciurba FC, Scharf SM, Sin DD, Voelker H, Washko GR, Woodruff PG and Lazarus SC: Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med, 2014; 370: 2201-2210
22) Schenk P, Spiel AO, Hüttinger F, Gmeiner M, Fugger J, Pichler M, Pichler G, Schmeikal S, Janistyn W, Schügerl S, Sajdik C and Herkner H: Can simvastatin reduce COPD exacerbations? A randomised double-blind controlled study. Eur Respir J, 2021; 58: 2001798
23) Papi A, Brightling C, Pedersen SE and Reddel HK: Asthma. Lancet, 2018; 391: 783-800
24) Fergeson JE, Patel SS and Lockey RF: Acute asthma, prognosis, and treatment. J Allergy Clin Immunol, 2017; 139: 438-447
25) Li W-J, Zhao Y, Gao Y, Dong L-L, Wu Y-F, Chen Z-H and Shen H-H: Lipid metabolism in asthma: Immune regulation and potential therapeutic target. Cell Immunol, 2021; 364: 104341
26) Hallstrand TS and Henderson WR, Jr.: An update on the role of leukotrienes in asthma. Curr Opin Allergy Clin Immunol, 2010; 10: 60-66
27) McCravy M, Ingram JL and Que LG: Dysregulated Metabolism in the Pathophysiology of Non-Allergic Obese Asthma. J Asthma Allergy, 2021; 14: 179-186
28) Akinbami LJ and Fryar CD: Current Asthma Prevalence by Weight Status Among Adults: United States, 2001-2014. NCHS Data Brief, 2016; 1-8
29) Witte A, Türk Y and Braunstahl GJ: Obesity-related asthma: new insights leading to a different approach. Curr Opin Pulm Med, 2024; 30: 294-302
30) de Boer GM, Tramper-Stranders GA, Houweling L, van Zelst CM, Pouw N, Verhoeven GT, Boxma-de Klerk BM, In ‘t Veen J, van Rossum EFC, Hendriks RW and Braunstahl GJ: Adult but not childhood onset asthma is associated with the metabolic syndrome, independent from body mass index. Respir Med, 2021; 188: 106603
31) van Zelst CM, de Boer GM, Türk Y, van Huisstede A, In’t Veen J, Birnie E, Boxma-de Klerk BM, Tramper-Stranders GA and Braunstahl GJ: Association between elevated serum triglycerides and asthma in patients with obesity: An explorative study. Allergy Asthma Proc, 2021; 42: e71-e76
32) Staggers KA, Minard C, Byers M, Helmer DA and Wu TD: Metabolic Dysfunction, Triglyceride-Glucose Index, and Risk of Severe Asthma Exacerbation. J Allergy Clin Immunol Pract, 2023; 11: 3700-3705.e3702
33) Lee HY, Lee EG, Hur J, Rhee CK, Kim YK, Lee SY and Kang JY: Pravastatin alleviates allergic airway inflammation in obesity-related asthma mouse model. Exp Lung Res, 2019; 45: 275-287
34) Zhang QX, Zhang HF, Lu XT, Zhao J and Xu QX: Statins improve asthma symptoms by suppressing inflammation: a meta-analysis based on RCTs. Eur Rev Med Pharmacol Sci, 2022; 26: 8401-8410
35) Lederer DJ and Martinez FJ: Idiopathic Pulmonary Fibrosis. N Engl J Med, 2018; 378: 1811-1823
36) Natsuizaka M, Chiba H, Kuronuma K, Otsuka M, Kudo K, Mori M, Bando M, Sugiyama Y and Takahashi H: Epidemiologic survey of Japanese patients with idiopathic pulmonary fibrosis and investigation of ethnic differences. Am J Respir Crit Care Med, 2014; 190: 773-779
37) Phan THG, Paliogiannis P, Nasrallah GK, Giordo R, Eid AH, Fois AG, Zinellu A, Mangoni AA and Pintus G: Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis. Cell Mol Life Sci, 2021; 78: 2031-2057
38) Richeldi L, Kolb M, Jouneau S, Wuyts WA, Schinzel B, Stowasser S, Quaresma M and Raghu G: Efficacy and safety of nintedanib in patients with advanced idiopathic pulmonary fibrosis. BMC Pulm Med, 2020; 20: 3
39) King TE, Jr., Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ and Noble PW: A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med, 2014; 370: 2083-2092
40) Raghu G, Amatto VC, Behr J and Stowasser S: Comorbidities in idiopathic pulmonary fibrosis patients: a systematic literature review. Eur Respir J, 2015; 46: 1113-1130
41) Lee JH, Park HJ, Kim S, Kim YJ and Kim HC: Epidemiology and comorbidities in idiopathic pulmonary fibrosis: a nationwide cohort study. BMC Pulm Med, 2023; 23: 54
42) Andreikos D, Karampitsakos T, Tzouvelekis A and Stratakos G: Statins’ still controversial role in pulmonary fibrosis: What does the evidence show? Pulm Pharmacol Ther, 2022; 77: 102168
43) Lee YJ, Kang N, Nam J, Lee EG, Ryoo J, Kwon SS, Kim YH and Kang HS: The preventative effects of statin on lung cancer development in patients with idiopathic pulmonary fibrosis using the National Health Insurance Service Database in Korea. PLoS One, 2024; 19: e0299484
44) Park J, Lee CH, Han K and Choi SM: Association between statin use and the risk for idiopathic pulmonary fibrosis and its prognosis: a nationwide, population-based study. Sci Rep, 2024; 14: 7805
45) Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I and Jemal A: Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024; May-Jun; 74: 229-263
46) Reck M and Rabe KF: Precision Diagnosis and Treatment for Advanced Non-Small-Cell Lung Cancer. N Engl J Med, 2017; 377: 849-861
47) O’Keeffe LM, Taylor G, Huxley RR, Mitchell P, Woodward M and Peters SAE: Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. BMJ Open, 2018; 8: e021611
48) Sin S, Lee CH, Choi SM, Han KD and Lee J: Metabolic Syndrome and Risk of Lung Cancer: An Analysis of Korean National Health Insurance Corporation Database. J Clin Endocrinol Metab, 2020; 105: dgaa596
49) Kucharska-Newton AM, Rosamond WD, Schroeder JC, McNeill AM, Coresh J and Folsom AR: HDL-cholesterol and the incidence of lung cancer in the Atherosclerosis Risk in Communities (ARIC) study. Lung Cancer, 2008; 61: 292-300
50) Ma C, Wang X, Guo J and Liu P: Prognostic significance of preoperative serum triglycerides and high-density lipoproteins cholesterol in patients with non-small cell lung cancer: a retrospective study. Lipids Health Dis, 2021; 20: 69
51) Li M, Cao SM, Dimou N, Wu L, Li JB and Yang J: Association of Metabolic Syndrome With Risk of Lung Cancer: A Population-Based Prospective Cohort Study. Chest, 2024; 165: 213-223
52) Duan P, Hu C, Quan C, Yi X, Zhou W, Yuan M, Yu T, Kourouma A and Yang K: Body mass index and risk of lung cancer: Systematic review and dose-response meta-analysis. Sci Rep, 2015; 5: 16938
53) Kawai S, Lin Y, Tsuge H, Ito H, Matsuo K, Wada K, Nagata C, Narii N, Kitamura T, Utada M, Sakata R, Kimura T, Tamakoshi A, Sugawara Y, Tsuji I, Suzuki S, Sawada N, Tsugane S, Mizoue T, Oze I, Abe SK and Inoue M: Body mass index and lung cancer risk: Pooled analysis of 10 prospective cohort studies in Japan. Cancer Sci, 2024; 115: 1346-1359
54) Benjamin DJ, Haslam A and Prasad V: Cardiovascular/anti-inflammatory drugs repurposed for treating or preventing cancer: A systematic review and meta-analysis of randomized trials. Cancer Med, 2024; 13: e7049
55) Rossi A, Filetti M, Taurelli Salimbeni B, Piras M, Rizzo F, Giusti R and Marchetti P: Statins and immunotherapy: Togetherness makes strength The potential effect of statins on immunotherapy for NSCLC. Cancer Rep (Hoboken), 2021; 4: e1368
56) Prina E, Ranzani OT and Torres A: Community-acquired pneumonia. Lancet, 2015; 386: 1097-1108
57) Musher DM and Thorner AR: Community-acquired pneumonia. N Engl J Med, 2014; 371: 1619-1628
58) GBD 2021 Diseases and Injuries Collaborators: Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990-2013; 2021: a systematic analysis for the Global Burden of Disease Study 2021. The Lancet, 2024; 403: 2133-2161
59) Morimoto K, Suzuki M, Ishifuji T, Yaegashi M, Asoh N, Hamashige N, Abe M, Aoshima M and Ariyoshi K: The burden and etiology of community-onset pneumonia in the aging Japanese population: a multicenter prospective study. PLoS One, 2015; 10: e0122247
60) Torres A, Peetermans WE, Viegi G and Blasi F: Risk factors for community-acquired pneumonia in adults in Europe: a literature review. Thorax, 2013; 68: 1057-1065
61) Hofmaenner DA, Kleyman A, Press A, Bauer M and Singer M: The Many Roles of Cholesterol in Sepsis: A Review. Am J Respir Crit Care Med, 2022; 205: 388-396
62) Taylor R, Zhang C, George D, Kotecha S, Abdelghaffar M, Forster T, Santos Rodrigues PD, Reisinger AC, White D, Hamilton F, Watkins WJ, Griffith DM and Ghazal P: Low circulatory levels of total cholesterol, HDL-C and LDL-C are associated with death of patients with sepsis and critical illness: systematic review, meta-analysis, and perspective of observational studies. EBioMedicine, 2024; 100: 104981
63) Chien YF, Chen CY, Hsu CL, Chen KY and Yu CJ: Decreased serum level of lipoprotein cholesterol is a poor prognostic factor for patients with severe community-acquired pneumonia that required intensive care unit admission. J Crit Care, 2015; 30: 506-510
64) Yousufuddin M, Sharma UM, Bhagra S and Murad MH: Hyperlipidaemia and mortality among patients hospitalised with pneumonia: retrospective cohort and propensity score matched study. BMJ Open Respir Res, 2021; 8: e000757
65) Batais MA, Khan AR and Bin Abdulhak AA: The Use of Statins and Risk of Community-Acquired Pneumonia. Curr Infect Dis Rep, 2017; 19: 26
66) Chalmers JD, Short PM, Mandal P, Akram AR and Hill AT: Statins in community acquired pneumonia: Evidence from experimental and clinical studies. Respir Med, 2010; 104: 1081-1091
67) World Health Organization, Global tuberculosis report 2023, https: //www.who.int/publications/i/item/9789240083851, 2023 (accessed 5/16 2024)
68) Wulandari DA, Hartati YW, Ibrahim AU, Pitaloka DAE and Irkham: Multidrug-resistant tuberculosis. Clin Chim Acta, 2024; 559: 119701
69) Pieters J: Mycobacterium tuberculosis and the macrophage: maintaining a balance. Cell Host Microbe, 2008; 3: 399-407
70) Sester M, van Leth F, Bruchfeld J, Bumbacea D, Cirillo DM, Dilektasli AG, Domínguez J, Duarte R, Ernst M, Eyuboglu FO, Gerogianni I, Girardi E, Goletti D, Janssens JP, Julander I, Lange B, Latorre I, Losi M, Markova R, Matteelli A, Milburn H, Ravn P, Scholman T, Soccal PM, Straub M, Wagner D, Wolf T, Yalcin A and Lange C: Risk assessment of tuberculosis in immunocompromised patients. A TBNET study. Am J Respir Crit Care Med, 2014; 190: 1168-1176
71) Ngo MD, Bartlett S and Ronacher K: Diabetes-Associated Susceptibility to Tuberculosis: Contribution of Hyperglycemia vs. Dyslipidemia. Microorganisms, 2021; 9: 2282
72) Jo YS, Han K, Kim D, Yoo JE, Kim Y, Yang B, Choi H, Sohn JW, Shin DW and Lee H: Relationship between total cholesterol level and tuberculosis risk in a nationwide longitudinal cohort. Sci Rep, 2021; 11: 16254
73) Deniz O, Gumus S, Yaman H, Ciftci F, Ors F, Cakir E, Tozkoparan E, Bilgic H and Ekiz K: Serum total cholesterol, HDL-C and LDL-C concentrations significantly correlate with the radiological extent of disease and the degree of smear positivity in patients with pulmonary tuberculosis. Clin Biochem, 2007; 40: 162-166
74) Dong Z, Shi J, Dorhoi A, Zhang J, Soodeen-Lalloo AK, Tan W, Yin H, Sha W, Li W, Zheng R, Liu Z, Yang H, Qin L, Wang J, Huang X, Wu C, Kaufmann SHE and Feng Y: Hemostasis and Lipoprotein Indices Signify Exacerbated Lung Injury in TB With Diabetes Comorbidity. Chest, 2018; 153: 1187-1200
75) Chidambaram V, Zhou L, Ruelas Castillo J, Kumar A, Ayeh SK, Gupte A, Wang JY and Karakousis PC: Higher Serum Cholesterol Levels Are Associated With Reduced Systemic Inflammation and Mortality During Tuberculosis Treatment Independent of Body Mass Index. Front Cardiovasc Med, 2021; 8: 696517
76) Gatfield J and Pieters J: Essential role for cholesterol in entry of mycobacteria into macrophages. Science, 2000; 288: 1647-1650
77) Bartlett S, Gemiarto AT, Ngo MD, Sajiir H, Hailu S, Sinha R, Foo CX, Kleynhans L, Tshivhula H, Webber T, Bielefeldt-Ohmann H, West NP, Hiemstra AM, MacDonald CE, Christensen LVV, Schlesinger LS, Walzl G, Rosenkilde MM, Mandrup-Poulsen T and Ronacher K: GPR183 Regulates Interferons, Autophagy, and Bacterial Growth During Mycobacterium tuberculosis Infection and Is Associated With TB Disease Severity. Front Immunol, 2020; 11: 601534
78) Soh AZ, Chee CB, Wang YT, Yuan JM and Koh WP: Dietary Cholesterol Increases the Risk whereas PUFAs Reduce the Risk of Active Tuberculosis in Singapore Chinese. J Nutr, 2016; 146: 1093-1100
79) Pérez-Guzmán C, Vargas MH, Quiñonez F, Bazavilvazo N and Aguilar A: A cholesterol-rich diet accelerates bacteriologic sterilization in pulmonary tuberculosis. Chest, 2005; 127: 643-651
80) Kang YA, Choi NK, Seong JM, Heo EY, Koo BK, Hwang SS, Park BJ, Yim JJ and Lee CH: The effects of statin use on the development of tuberculosis among patients with diabetes mellitus. Int J Tuberc Lung Dis, 2014; 18: 717-724
81) Su VY, Su WJ, Yen YF, Pan SW, Chuang PH, Feng JY, Chou KT, Yang KY, Lee YC and Chen TJ: Statin Use Is Associated With a Lower Risk of TB. Chest, 2017; 152: 598-606
82) Daley CL, Iaccarino JM, Lange C, Cambau E, Wallace RJ, Jr., Andrejak C, Böttger EC, Brozek J, Griffith DE, Guglielmetti L, Huitt GA, Knight SL, Leitman P, Marras TK, Olivier KN, Santin M, Stout JE, Tortoli E, van Ingen J, Wagner D and Winthrop KL: Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline. Clinical Infectious Diseases, 2020; 71: e1-e36
83) Prevots DR and Marras TK: Epidemiology of human pulmonary infection with nontuberculous mycobacteria: a review. Clin Chest Med, 2015; 36: 13-34
84) Tokuda H, Harigai M, Kameda H, Tomono K, Takayanagi N, Watanabe A, Tasaka S, Suda T, Tateda K and Kadota J: Consensus statements for medical practice: Biological agents and lung disease [Abridged English translation by the Japanese Respiratory Society]. Respir Investig, 2017; 55: 229-251
85) Kumar K and Loebinger MR: Nontuberculous Mycobacterial Pulmonary Disease: Clinical Epidemiologic Features, Risk Factors, and Diagnosis: The Nontuberculous Mycobacterial Series. Chest, 2022; 161: 637-646
86) Chan ED and Iseman MD: Slender, older women appear to be more susceptible to nontuberculous mycobacterial lung disease. Gend Med, 2010; 7: 5-18
87) Hong JY, Yang GE, Ko Y, Park YB, Sim YS, Park SH, Lee CY, Jung KS and Lee MG: Changes in cholesterol level correlate with the course of pulmonary nontuberculous mycobacterial disease. J Thorac Dis, 2016; 8: 2885-2894
88) Ikegame S, Maki S, Wakamatsu K, Nagata N, Kumazoe H, Fujita M, Nakanishi Y, Kawasaki M and Kajiki A: Nutritional Assessment in Patients with Pulmonary Nontuberculous Mycobacteriosis. Internal Medicine, 2011; 50: 2541-2546
89) Wakamatsu K, Nagata N, Maki S, Omori H, Kumazoe H, Ueno K, Matsunaga Y, Hara M, Takakura K, Fukumoto N, Ando N, Morishige M, Akasaki T, Inoshima I, Ise S, Izumi M and Kawasaki M: Patients with MAC Lung Disease Have a Low Visceral Fat Area and Low Nutrient Intake. Pulmonary Medicine, 2015; 2015: 218253
90) Crilly NP, Ayeh SK and Karakousis PC: The New Frontier of Host-Directed Therapies for Mycobacterium avium Complex. Front Immunol, 2020; 11: 623119
91) World Health Organization, Statement on the fifteenth meeting of the IHR (2005) Emergency Committee on the COVID-19 pandemic, https: //www.who.int/news/item/05-05-2023-statement-on-the-fifteenth-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-coronavirus-disease-(covid-19)-pandemic, 2023 (accessed 5/16 2024)
92) Dissanayake H: COVID-19 and metabolic syndrome. Best Pract Res Clin Endocrinol Metab, 2023; 37: 101753
93) Rico-Martín S, Calderón-García JF, Basilio-Fernández B, Clavijo-Chamorro MZ and Sánchez Muñoz-Torrero JF: Metabolic Syndrome and Its Components in Patients with COVID-19: Severe Acute Respiratory Syndrome (SARS) and Mortality. A Systematic Review and Meta-Analysis. J Cardiovasc Dev Dis, 2021; 8: 162
94) Atmosudigdo IS, Lim MA, Radi B, Henrina J, Yonas E, Vania R and Pranata R: Dyslipidemia Increases the Risk of Severe COVID-19: A Systematic Review, Meta-analysis, and Meta-regression. Clin Med Insights Endocrinol Diabetes, 2021; 14: 1179551421990675
95) Choi GJ, Kim HM and Kang H: The Potential Role of Dyslipidemia in COVID-19 Severity: an Umbrella Review of Systematic Reviews. J Lipid Atheroscler, 2020; 9: 435-448
96) Lorizate M and Kräusslich HG: Role of lipids in virus replication. Cold Spring Harb Perspect Biol, 2011; 3: a004820
97) Lao US, Law CF, Baptista-Hon DT and Tomlinson B: Systematic Review and Meta-Analysis of Statin Use and Mortality, Intensive Care Unit Admission and Requirement for Mechanical Ventilation in COVID-19 Patients. J Clin Med, 2022; 11: 5454
98) Zein A, Sulistiyana CS, Khasanah U, Wibowo A, Lim MA and Pranata R: Statin and mortality in COVID-19: a systematic review and meta-analysis of pooled adjusted effect estimates from propensity-matched cohorts. Postgrad Med J, 2022; 98: 503-508
99) Hills TE, Lorenzi E, Berry LR, Shyamsundar M, Al-Beidh F, Annane D, Arabi Y, Aryal D, Au C, Beane A, Bhimani Z, Bonten M, Bradbury CA, Brunkhorst FM, Burrell A, Buxton M, Calfee CS, Cecconi M, Cheng AC, Cove ME, Detry MA, Estcourt LJ, Fitzgerald M, Goligher EC, Goossens H, Green C, Haniffa R, Harrison DA, Hashmi M, Higgins AM, Huang DT, Ichihara N, Jayakumar D, Kruger PS, Lamontagne F, Lampro L, Lawler PR, Marshall JC, Mason AJ, McGlothlin A, McGuinness S, McQuilten ZK, McVerry BJ, Mouncey PR, Murthy S, Neal MD, Nichol AD, O’Kane CM, Parke RL, Parker JC, Rabindrarajan E, Reyes LF, Rowan KM, Saito H, Santos M, Saunders CT, Seymour CW, Shankar-Hari M, Sinha P, Thompson BT, Turgeon AF, Turner AM, van de Veerdonk F, Weis S, Young IS, Zarychanski R, Lewis RJ, McArthur CJ, Angus DC, Berry SM, Derde LPG, Webb SA, Gordon AC and McAuley DF: Simvastatin in Critically Ill Patients with Covid-19. N Engl J Med, 2023; 389: 2341-2354
